2. Academic Validation
  3. In vitro safety signals for potential clinical development of the anti-inflammatory pregnane X receptor agonist FKK6

In vitro safety signals for potential clinical development of the anti-inflammatory pregnane X receptor agonist FKK6

  • Bioorg Chem. 2024 Mar:144:107137. doi: 10.1016/j.bioorg.2024.107137.
Zdeněk Dvořák 1,  Barbora Vyhlídalová 2,  Petra Pečinková 2,  Hao Li 3,  Pavel Anzenbacher 4,  Alena Špičáková 4,  Eva Anzenbacherová 5,  Vimanda Chow 6,  Jiabao Liu 7,  Henry Krause 7,  Derek Wilson 6,  Tibor Berés 8,  Petr Tarkowski 9,  Dajun Chen 10,  Sridhar Mani 11
Affiliations

Affiliations

  • 1 Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic. Electronic address: zdenek.dvorak@upol.cz.
  • 2 Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic.
  • 3 Department of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 4 Department of Pharmacology, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 779 00 Olomouc, Czech Republic.
  • 5 Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 779 00 Olomouc, Czech Republic.
  • 6 Department of Chemistry, York University, 6 Thompson Road, M3J 1L3, ON, Toronto, Canada.
  • 7 Department of Molecular Genetics, Donnelly Centre for Cellular and Biomolecular Research, 160 College Street, M5S 3E1, ON, Toronto, Canada.
  • 8 Czech Advanced Technology and Research Institute, Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic.
  • 9 Czech Advanced Technology and Research Institute, Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech Republic; Department of Genetic Resources for Vegetables, Medicinal and Special Plants, Centre of the Region Haná for Biotechnological and Agricultural Research, Crop Research Institute, Šlechtitelů 27, 783 71 Olomouc, Czech Republic.
  • 10 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 11 Department of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: sridhar.mani@einsteinmed.edu.
PMID: 38245951 DOI: 10.1016/j.bioorg.2024.107137
Abstract

Based on the mimicry of microbial metabolites, functionalized indoles were demonstrated as the ligands and agonists of the pregnane X receptor (PXR). The lead indole, FKK6, displayed PXR-dependent protective effects in DSS-induced colitis in mice and in vitro cytokine-treated intestinal Organoid cultures. Here, we report on the initial in vitro pharmacological profiling of FKK6. FKK6-PXR interactions were characterized by hydrogen-deuterium exchange mass spectrometry. Screening FKK6 against potential cellular off-targets (G protein-coupled receptors, steroid and nuclear receptors, ion channels, and xenobiotic membrane transporters) revealed high PXR selectivity. FKK6 has poor aqueous solubility but was highly soluble in simulated gastric and intestinal fluids. A large fraction of FKK6 was bound to plasma proteins and chemically stable in plasma. The partition coefficient of FKK6 was 2.70, and FKK6 moderately partitioned into red blood cells. In Caco2 cells, FKK6 displayed high permeability (A-B: 22.8 × 10-6 cm.s-1) and no active efflux. These data are indicative of essentially complete in vivo absorption of FKK6. The data from human liver microsomes indicated that FKK6 is rapidly metabolized by cytochromes P450 (t1/2 5 min), notably by CYP3A4. Two oxidized FKK6 derivatives, including DC73 (N6-oxide) and DC97 (C19-phenol), were detected, and these metabolites had 5-7 × lower potency as PXR agonists than FKK6. This implies that despite high intestinal absorption, FKK6 is rapidly eliminated by the liver, and its PXR effects are predicted to be predominantly in the intestines. In conclusion, the PXR ligand and agonist FKK6 has a suitable pharmacological profile supporting its potential preclinical development.

Keywords

Absorption; Distribution; Metabolism; Off targets; Pre-clinical evaluation; Pregnane X receptor; Toxicokinetics.

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